Project Summary Nearly 9 in 10 Americans will be exposed to trauma in their lifetime and 1 in 10 will develop post-traumatic stress disorder (PTSD), which is characterized by elevated threat (e.g., intrusions, anxious arousal), loss (e.g., anhedonia, negative affect) and neurocognitive (e.g., verbal learning, attention) symptoms. Individuals with PTSD have elevated rates of physical health conditions, as well as functional impairment, with loss symptoms in particular contributing to decreased quality of life. The immune system is responsible for maintaining health, which includes mounting a response to physical (e.g., virus, injury) and psychological (e.g., stress) insults, as well as modulating the progression of neurodegenerative disorders such as Alzheimer?s disease. All of these - physical health conditions, psychological distress, and neurodegenerative disorders - are more prevalent in individuals with than without PTSD. There are peripheral immune system abnormalities in PTSD; however, no known study has evaluated the role of the neuroimmune system in PTSD. In the healthy immune system, the response of the central nervous system to an insult or damage is mediated by the activation of microglia, which carry out repair functions. However, excessive activation can lead to neuronal dysfunction and damage through the release of inflammatory cytokines and stress hormones, and may contribute to neurodegeneration, such as that found in individuals with PTSD. When microglia are activated, there is a robust increase in the expression of translocator protein (TSPO). Positron emission tomography (PET) radiotracers such as [11C]PBR28, which bind to TSPO, can therefore be used to measure levels of activated microglia in vivo. In addition to measuring levels of activated microglia in individuals with PTSD (vs. controls), we can also challenge the immune system by administering E. Coli lipopolysaccharide (LPS), a potent immune activator and measure increases in activated microglia within subject. We have recently demonstrated robust LPS- induced increases in activated microglia, and concomitant increases in peripheral inflammatory cytokines, and associated mood, anxiety, and neurocognitive symptoms in humans. In the proposed study, we will systematically evaluate the relationship between ?neuroinflammation?, as assessed with [11C]PBR28 and PET, and the expression of threat, loss, and neurocognitive symptoms in 80 trauma-exposed individuals presenting with the full dimensional spectrum of PTSD symptoms. Specifically, we will (1) determine whether individuals with PTSD have higher levels of activated microglia compared to trauma-exposed controls; (2) use a novel neuroimmune ?stress test? to determine whether individuals with PTSD have a dysfunctional neuroimmune response to systemic administration of LPS; and (3) determine the role of activated microglia in mediating the relationship between peripheral inflammatory markers (e.g., TNF-?), and trauma-related symptoms to discover potential biomarkers of PTSD. Results of this study will yield insight into novel, mechanism-based, and treatable neuroimmune mechanisms implicated in PTSD and related syndromes.